1. Field of The Invention
The present invention relates generally to medical devices and methods. More particularly, the present invention relates to improved devices and methods for removing cerebrospinal fluid (CSF) from the CSF space of a patient to treat Alzheimer""s disease and other diseases.
Alzheimer""s disease is a degenerative brain disorder which is characterized clinically by progressive loss of memory, cognition, reasoning, judgment, and emotional stability and which gradually leads to profound mental deterioration and ultimately death. Alzheimer disease is the most common cause of progressive mental failure (dementia) in aged humans and is estimated to represent the fourth most common medical cause of death in the United States. Alzheimer""s disease has been observed in all races and ethnic groups worldwide and presents a major current and future public health problem. The disease is currently estimated to affect about two to four million individuals in the United States alone and is presently considered to be incurable.
Recently, a promising treatment for Alzheimer""s disease has been proposed. The proposed treatment relies on the removal of cerebrospinal fluid (CSF) from the CSF space (which includes the subarachnoid space, the ventricles, the vertebral column, and the brain interstitial space) of a patient suffering from Alzheimer""s disease. The treatment is based on the principle that in at least some cases, the characteristic lesions, referred to as senile (or amyloid) plaque and other characteristic lesions in the brain associated with Alzheimer""s disease result from the retention of certain toxic substances in the CSF of the patient. A number of suspected pathogenic substances, including toxic, neurotoxic, and pathogenic substances, have been identified to date, including xcex2-amyloid peptide (Axcex2-42 amyloid), MAP, tau, and the like. It is believed that freshly produced CSF has lower levels or is free of these toxic substances. Thus, it is believed that removal of CSF from the patient""s CSF space will reduce the concentration of such substances and significantly forestall the onset and/or progression of Alzheimer""s disease. This treatment for Alzheimer""s disease has recently been described in Rubenstein (1998) The Lancet, 351:283-285, and published PCT application WO 98/02202.
Hydrocephalus is another condition which is treated by removing CSF from a patient""s CSF space, in particular from the cerebral ventricles. Hydrocephalus is characterized by an elevated intracranial pressure resulting from excessive production or retention of CSF, and the removal of such excess CSF has been found to be a highly effective treatment for the condition. Numerous specific catheters and shunts have been designed and produced for the treatment of hydrocephalus, occult hydrocephalus, and other CSF disorders.
The removal of CSF for the treatment of either Alzheimer""s disease or hydrocephalus can be accomplished using a wide variety of apparatus which are capable of collecting CSF in the CSF space, preferably from the intracranial ventricles, and transporting the collected fluid to a location outside of the CSF space. Usually, the location will be an internal body location, such as the venous system or the peritoneal cavity, which is capable of harmlessly receiving the fluid and any toxic substances, but it is also possible to externally dispose of the CSF using a transcutaneous device. An exemplary system for removing CSF from a patient""s CSF space is illustrated in FIG. 1 and includes an access component 12, a disposal component 14, and a flow control component 16.
While the system of FIG. 1 in general will be suitable for the treatment of both Alzheimer""s disease and hydrocephalus, specific characteristics of the flow control component should be quite different because of the different nature of the two diseases. Treatment of hydrocephalus is best accomplished by controlling the flow rate of CSF from the CSF space to the disposal location in order to maintain intracranial pressure within normal physiological limits. Particularly suitable flow control characteristics for a flow control module in a hydrocephalus treatment system are illustrated in FIG. 2. FIG. 2 is taken from U.S. Pat. No. 4,781,672 which describes a flow control valve of the type used in the commercially available Orbis-Sigma(copyright) valve unit available from Nitinol Medical Technologies, Inc. Boston, Mass., 02210 (formerly from Cordis, Miami, Fla.). Briefly, the pressure P is the differential pressure between the CSF space and the disposal location. The patent teaches that the control valve establishes an initial flow rate Q1 of about 0.4 ml/min when the differential pressure P reaches an initial level P1 of 80 mm H2O and increases to a higher flow rate Q2 of 0.8 ml/min as the differential pressure increases to a higher value P2 of 350 mm H2O. When pressure P is below P1, there is essentially no flow. At pressures above P2, the flow is essentially unrestricted. Such valve flow characteristic are particularly suitable for treating hydrocephalus because for pressures below P1, there is no need to reduce pressure and thus no need to remove CSF. For pressures from P1 to P2, a controlled removal of CSF is desired to lower intracranial pressure with minimum risk of removing excessive amounts of CSF. When intracranial pressure exceeds P2 rapid removal of CSF is necessary to immediately lower intracranial pressure to a safer level. Such previous systems for draining CSF from the CSF space of the patient are generally not suitable for the treatment of patients suffering from Alzheimer""s disease or other conditions relating to toxic substances in the CSF.
For these reasons, it would be desirable to provide devices and methods for removing CSF from the CSF space of a patient, where such devices and methods are particularly modified and optimized for treating Alzheimer""s disease and other conditions relating to toxic substances in cerebrospinal fluid. Such devices and methods will preferably provide for the controlled removal of CSF from the patient in a manner which effectively removes the toxic substances to reduced levels without excessive removal of the CSF in a manner which places the patient at risk. Such objective will be met at least in part by the invention described hereinafter.
2. Description of Background Art
The treatment of Alzheimer""s disease by removing cerebrospinal fluid from the CSF region of the brain is described in co-pending applications U.S. Ser. No. 08/678,191 now U.S. Pat. No. 5,908,480, filed on Jul. 11, 1996, and U.S. Ser. No. 08/901,023 now U.S. Pat. No. 6,264,625, filed on Jul. 25, 1997, both of which are assigned to the assignee of the present invention. The full disclosures of each of these two applications are incorporated herein by reference. The latter application is equivalent to WO 98/02202.
Methods and shunts for treating hydrocephalus are described in U.S. Pat. Nos. 3,889,687; 3,985,140; 3,913,587; 4,375,816; 4,377,169; 4,385,636; 4,432,853; 4,532,932; 4,540,400; 4,551,128; 4,557,721; 4,576,035; 4,595,390; 4,598,579; 4,601,721; 4,627,832; 4,631,051; 4,675,003; 4,676,772; 4,681,559; 4,705,499; 4,714,458; 4,714,459; 4,769,002; 4,776,838; 4,781,672; 4,787,886; 4,850,955; 4,861,331; 4,867,740; 4,931,039; 4,950,232; 5,039,511; 5,069,663; 5,336,166; 5,368,556; 5,385,541; 5,387,188; 5,437,627; 5,458,606; PCT Publication WO 96/28200; European Publication 421558; 798011; and 798012; French Publication 2 705 574; Swedish Publication 8801516; and SU 1297870. A comparison of the pressure-flow performance of a number of commercially available hydrocephalus shunt devices is presented in Czosnyka et al. (1998) Neurosurgery 42: 327-334. A shunt valve having a three-stage pressure response profile is sold under the Orbis-Sigma(copyright) tradename by Nitinol Medical Technologies, Inc. Boston, Mass. 02210 (formerly by Cordis). U.S. Pat. No. 5,334,315, describes treatment of various body fluids, including cerebrospinal fluids, to remove pathogenic substances therefrom.
Articles discussing pressures and other characteristics of CSF in the CSF space include Condon (1986) J. Comput. Assit. Tomogr. 10:784-792; Condon (1987) J. Comput. Assit. Tomogr. 11:203-207; Chapman (1990) Neurosurgery 26:181-189; Magneas (1976) J. Neurosurgery 44:698-705; Langfitt (1975) Neurosurgery 22:302-320.
Devices and methods according to the present invention provide for the controlled and optimized removal of cerebrospinal fluid (CSF) from the CSF space of a patient. The devices and methods are particularly intended for the treatment of Alzheimer""s disease and other conditions which are caused by or otherwise related to the retention and accumulation of toxic substances in the CSF. In addition to Alzheimer""s disease, the present invention will be useful for treating other conditions resulting from the accumulation of toxic substances and resulting lesions in the patient""s brain, such as Down""s Syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch-Type (HCHWA-D), and the like. Other treatable conditions relating to the chronic or acute presence of potentially putative substances include epilepsy, narcolepsy, Parkinson""s disease, polyneuropathies, multiple sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis, muscular dystrophy, dystrophy myotonic, other myotonic syndromes, polymyositis, dermatomyositis, brain tumors, Guillain-Barre-Syndrome, and the like.
Devices and methods of the present invention are intended for treating conditions in patients having xe2x80x9cnormalxe2x80x9d intracranial pressures, i.e. intracranial pressures below 200 mm H2O when the patient is reclining and above xe2x88x92170 mm H2O when the patient is upright (where the pressures are measured relative to the ambient). In contrast, patients suffering from hydrocephalus will have constant or periodic elevated intracranial pressures above 200 mm H2O (when reclining), often attaining levels two or three times the normal level if untreated. The devices and methods of the present invention are not intended for the treatment of patients having elevated intracranial pressures in general and patients suffering from hydrocephalus in particular.
The differences in untreated intracranial and ventricular pressures as well as the different treatment end points (the treatment of hydrocephalus requires lowering of elevated pressures while treatments according to present inventions require lowering of the concentrations of substances in the CSF) require significantly different treatment devices and methods. In particular, treatments and methods according to present invention rely on relatively low CSF removal rates, usually in the range from 0.01 ml/min to 0.2 ml/min, more usually in the range from 0.03 ml/min to 0.1 ml/min, and preferably in the range from 0.04 ml/min to 0.06 ml/min. Further preferably, CSF removal at such low rates will occur continuously or at least so long as the intracranial and ventricular pressures do not fall below certain minimal levels, e.g. below about xe2x88x92170 mm H2O. Such safety thresholds correspond generally to the lowest expected ventricular pressure of the patient when upright. The intracranial and ventricular pressures referred to above are defined or measured as xe2x80x9cgaugexe2x80x9d pressures, i.e. relative to ambient. The intracranial pressure falls below ambient (O mmH2O) as a result of the compliant nature of the CSF space and the column of CSF fluid which is created as the patient sits upright or stands. The ability of the flow control module to maintain a relatively constant flow (as defined below) regardless of the variations in the intracranial or ventricular xe2x80x9csourcexe2x80x9d pressure is an important aspect of the present invention.
The CSF removal techniques of the present invention generally rely on pressure-compensated removal to achieve the desired constant flow rate, where the generally constant (usually varying by no more than xc2x175%, preferably no more than xc2x150%, and more preferably xc2x120%) removal rate is achieved by providing a pressure-controlled variable resistance path in the flow control module between the CSF space and the disposal site. In contrast, the flow control valves for hydrocephalus treatment, such as those described in U.S. Pat. No. 4,781,672, intentionally provide for significant variation in flow rate as the pressure differential across the flow valve passes through specific control points. Use by the present invention of a generally constant flow rate which is below the normal CSF production rate minimizes the possibility of over removal of the CSF and the risk of occlusion associated with CSF stagnation.
In a first aspect, methods for reducing the concentrations of toxic substances in CSF comprise establishing a drain path from a CSF space in the patient, typically a ventricle in the brain. The drain path is configured or defined to remove CSF at a rate in the ranges set forth above while the intracranial pressure may vary over a relatively broad range, typically from xe2x88x92170 mm H2O to 200 mm H2O, depending on patient orientation. Usually, the CSF flow rate will vary by no more than xc2x175%, usually xc2x150%, and preferably xc2x120%, as the intracranial pressure varies over the above range.
The drain path may extend to any internal or external disposal location of a type commonly used with the treatment of hydrocephalus. Usually, the disposal location will be into the venous system, the peritoneal cavity (peritoneal space), the pleural cavity (pleural space), or the like. It will also be possible (although usually less desirable) to employ transcutaneous devices where disposal occurs to an external space outside of the patient""s body, e.g. into a drainage bag.
Apparatus according to present invention comprise access component, such as a catheter adapted to reside in the ventricle or other portion of the CSF space of the patient, (e.g., a lumbar space) and a flow control component connectable to an outlet of the access component. The flow control component will be adapted to control the CSF flow rate from the access component within the flow rate ranges set forth above, while the pressure in the CSF space varies over the range set forth above. In the illustrated embodiments, the flow control component will be passive, i.e. a pressure-compensated flow control valve. The present invention, however, also includes actively controlled flow control valves and pumps, where the valves and pumps can be powered by battery, patient movement, or the like. The apparatus may further comprise a disposal component connectable to an outlet of the flow control component. The disposal component will usually be adapted to further direct the drain path to a target disposal site, such as the venous system, peritoneal cavity, pleural cavity, or the like. Preferably, the flow control component will further be adapted to stop or greatly reduce the flow of CSF when intracranial pressure falls below the safety threshold set forth above.
In some instances, the apparatus may comprise the flow control module alone.
In a specific embodiment, the flow control module according to the present invention comprises a diaphragm valve connectable to an outlet of an access component. The diaphragm valve includes a pressure-responsive diaphragm, a contoured plug, and an orifice which receives the contoured plug and permits the flow of CSF therethrough. Either the plug or the orifice is coupled to move with the diaphragm in response to changes in the differential pressure across the valve. The contoured plug has a profile (or other modification) which is selected to provide a variable annular flow region between the plug and the orifice so that flow is controlled within the target range as set forth above while the intracranial pressure varies within the range set forth above. Usually, the orifice will be directly coupled to the diaphragm, while the plug is fixed relative to a valve body. The apparatus may further comprise an access component and/or a disposal component, which may be any of the components described above.